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Expression of the Chemokine Receptor Gene, CCR8, is Associated With DUSP22 Rearrangements in Anaplastic Large Cell Lymphoma

Xing, Xiaoming MD, PhD*,†; Flotte, Thomas J. MD*; Law, Mark E. BS*; Blahnik, Anthony J. BS*; Chng, Wee-Joo MD, PhD‡,§; Huang, Gaofeng PhD; Knudson, Ryan A. BS*; Ketterling, Rhett P. MD*; Porcher, Julie C. BS; Ansell, Stephen M. MD, PhD; Sidhu, Jagmohan MD; Dogan, Ahmet MD, PhD*; Feldman, Andrew L. MD*

Applied Immunohistochemistry & Molecular Morphology: September 2015 - Volume 23 - Issue 8 - p 580–589
doi: 10.1097/PAI.0000000000000118
Research Articles

Anaplastic large cell lymphoma (ALCL) is one of the most common T-cell non-Hodgkin lymphomas and has 2 main subtypes: an anaplastic lymphoma kinase (ALK)-positive subtype characterized by ALK gene rearrangements and an ALK-negative subtype that is poorly understood. We recently identified recurrent rearrangements of the DUSP22 locus on 6p25.3 in both primary cutaneous and systemic ALK-negative ALCLs. This study aimed to determine the relationship between these rearrangements and expression of the chemokine receptor gene, CCR8. CCR8 has skin-homing properties and has been suggested to play a role in limiting extracutaneous spread of primary cutaneous ALCLs. However, overexpression of CCR8 has also been reported in systemic ALK-negative ALCLs. As available antibodies for CCR8 have shown lack of specificity, we examined CCR8 expression using quantitative real-time PCR in frozen tissue and RNA in situ hybridization (ISH) in paraffin tissue. Both approaches showed higher CCR8 expression in ALCLs with DUSP22 rearrangements than in nonrearranged cases (PCR: 19.5-fold increase, P=0.01; ISH: 3.3-fold increase, P=0.0008). CCR8 expression was not associated with cutaneous presentation, cutaneous biopsy site, or cutaneous involvement during the disease course. These findings suggest that CCR8 expression in ALCL is more closely related to the presence of DUSP22 rearrangements than to cutaneous involvement and that the function of CCR8 may extend beyond its skin-homing properties in this disease. This study also underscores the utility of RNA-ISH as a paraffin-based method for investigating gene expression when reliable antibodies for immunohistochemical analysis are not available.

*Department of Laboratory Medicine and Pathology

Division of Hematology, Mayo Clinic, Rochester, MN

Department of Pathology, Affiliated Hospital of Medical College, Qingdao University, Qingdao, China

Department of Hematology-Oncology, National University Cancer Institute of Singapore

§Cancer Science Institute of Singapore, National University Cancer Institute of Singapore, Singapore, Singapore

Department of Pathology and Laboratory Medicine, United Health Services Hospitals, Johnson City/Binghamton, NY

Present address: Ahmet Dogan, MD, PhD, Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY.

Supported by the Center for Individualized Medicine and the Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, by Award Numbers R01 CA177734 (ALF) and P50 CA97274 (University of Iowa/Mayo Clinic Lymphoma SPORE), and National Cancer Institute. X.X. was supported by a scholarship award from the China Scholarship Council. A.L.F. is a Damon Runyon Clinical Investigator supported by the Damon Runyon Cancer Research Foundation (CI-48-09).

The authors declare no conflict of interest.

Reprints: Andrew L. Feldman, MD, Department of Laboratory Medicine and Pathology, Hilton Building, Room 8-00F, Mayo Clinic, 200 First St. SW, Rochester, MN 55905 (e-mail: feldman.andrew@mayo.edu).

Received April 28, 2014

Accepted May 21, 2014

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